The ability to maintain baseline function despite genetic and environmental perturbation is essential for the nervous system. At the neuromuscular junction, a perturbation to post-synaptic receptor function results in an increase of presynaptic neurotransmitter release, returning muscle excitation to baseline levels. This process is known as synaptic homeostasis and it is conserved from the fly to rat to human. It is hypothesized to play an important role in neurological diseases from autism to myasthenia gravis. Many key regulators of this process have yet to be identified. We propose research to characterize the fly class II PI3-kinase, a lipid kinase shown in preliminary experiments to be necessary for synaptic homeostasis. Unlike the better studied class I and class III PI3- kinases, class II PI3-kinases are not well understood in the nervous system. They have been shown to be important for clathrin mediated endocytosis and catecholamine release from neurosecretory cells. Through the two aims of this project, we will characterize the class II PI3-kinase in synaptic homeostasis. First, we will test the hypothesis that the fly class II PI3-kinase is necessary and sufficient for facilitating presynaptic release. Second, we will test the hypothesis that the class II PI3-kinase modulates presynaptic release by altering the readily releasable pool of vesicles. These experiments will allow us to better understand the mechanisms behind synaptic homeostasis, especially the role of lipid phosphorylation in the modulation of synaptic activity. It will provide the groundwork for studying class II PI3-kinases as therapeutic targets fr devastating neurologic diseases like autism, Alzheimer's disease, and myasthenia gravis.
Neurological diseases like epilepsy, autism, and myasthenia gravis are thought to be caused by a change in neuronal stability. The research we propose here will characterize a protein involved in neuronal stability and provide the backbone for research into this protein as a potential drug target for neurological diseases.
| Hauswirth, Anna G; Ford, Kevin J; Wang, Tingting et al. (2018) A postsynaptic PI3K-cII dependent signaling controller for presynaptic homeostatic plasticity. Elife 7: |
